PROJECT SUMMARY - TUMOR MICROENVIRONMENT AND METASTASIS PROGRAM Research in the Tumor Microenvironment and Metastasis (TMM) program is directed to defining the mechanisms by which the microenvironment initiates and sustains systemic dissemination of cancers based on interactions between tumor and stromal cells. Program goals include (i) identification of stromal cell types responsible for migratory and disseminating tumor cell phenotypes, (ii) development of in vitro models and cell lines to elucidate the mechanisms for stromal cell induction of tumor cell dissemination, and the discovery of prognostic markers based on these mechanisms, (iii) characterization of molecular mechanisms of growth factor and cytokine actions that regulate cell migration, dissemination, angiogenesis and invasion of distant sites by tumor cells through elucidating intrinsic regulatory, downstream mechanisms, (iv) elucidation of the role of surface molecules and their associated cytoskeletal proteins in tumor cell behavior and metastatic phenotype. A variety of systems are utilized, including cell lines in vitro, animal models in vivo and xenografts, transgenic mouse models of breast cancer and unique biophysical and cell biology tools. A unique aspect of this program is the development of innovative imaging technologies for the study of tumor microenvironment- driven metastasis in vivo that allows documentation of the longitudinal progression of cancers in all sites and stages. These studies encompass: (i) development of large-volume, high-resolution multiphoton intravital imaging to directly observe the initiation of tumors and their dissemination in order to elucidate the underlying mechanisms, (ii) the development of permanent imaging windows for primary and secondary sites for documentation of single cell phenotype, fate and contribution to metastasis, and (iii) the development of novel tumor indwelling microfluidic devices that deliver precise signals to the tumor microenvironment. The over- arching goal of this program, and a major focus since 2013, is the translation of basic mechanistic findings in the laboratory to mouse models with translation to correlative, preventive and therapeutic initiatives in the clinic. Ongoing clinical studies are focused on developing independent, novel correlates of risk of breast cancer progression and metastasis, along with pharmacological interventions in patients conducted by members of the Experimental Therapeutics program. Likewise, there are ongoing studies to translate MRI-based imaging technology from mouse models into imaging protocols in patients that will allow noninvasive in vivo assessment of metastatic risk and response to treatment. While a major focus of research has been on breast cancer, the TMM program now includes research in head and neck, thyroid, pancreatic and other cancers. There are 20 program members from 9 departments. Current NCI funding is 2.3M (dc); total peer-reviewed funding is 4.7M (dc). There have been 297 publications since July 2013 of which 23% represent intra- programmatic, 26% inter-programmatic, and 58% represent collaborations with investigators at other institutions.